Prostate cancer is the second most common cancer in men (after skin cancer), and the second leading cause of cancer death in men (after lung cancer). In the United States, there are greater than 300,000 newly diagnosed cases each year, and about 40,000 of patients die of the disease yearly (Stewart et al., 2004). Approximately 90% of patients with advanced prostate cancer develop osseous metastases. Once prostate cancer metastasizes to the bone it is difficult to eradicate, and typically, these patients have a mean survival time of nine months to one year (Stewart et al., 2004).
Approximately 30% of men over the age of 55 harbor latent prostate cancers, detectable only at postmortem examination. Greater than 95% of cancers of the prostate are gland-forming adenocarcinomas, which have a predilection for the peripheral zones. The remaining prostate cancers are divided between squamous cell and transitional cell carcinomas (arising from the prostatic ducts), small cell and other neuroendocrine tumors, and rarely, carcinosarcomas. The histologic precursor lesion of prostatic adenocarcinomas is prostatic intraepithelial neoplasia (PIN), which shares the cytological features of cancer as well as many of the associated genetic abnormalities. Unlike adenocarcinomas, PIN occurs within preexisting acinar structures, and is divided into low-grade (meaning slightly unusual) and high-grade (very unusual and close to being called cancer) variants. The latter is a more reproducible diagnosis and also has a stronger morphologic, genetic and clinical association with prostate cancer. In fact, the presence of isolated high-grade PIN in needle biopsy specimens strongly suggests that there is a co-existing carcinoma in the prostate.
Although a considerable proportion of prostate cancers grow slowly and are not considered to require urgent intervention, some grow quickly and are deadly. If these cancers are detected in early stages, such as Stages I and II, however, they can be effectively treated and cured. Combined with the digital rectal examination (DRE), the prostate specific antigen (PSA) test has been widely used to detect prostate cancer in its early stages. This test measures the serum levels of PSA, an enzyme that is produced by the prostate and released into the bloodstream to reach concentrations below 3-4 ng/ml in healthy individuals. PSA levels above that value are considered as an indication of possible prostate cancer. However, PSA is specific for prostate tissues, but not for prostate cancer. Multiple factors such as benign prostatic hyperplasia (BPH), prostatitis, prostatic ischemia or infarction, and even sexual activity can cause of elevated levels of PSA. Further, serum PSA levels are not a sensitive indicator for prostate cancer, as these may be normal despite the presence of the disease (Thompson et al., 2004).
Thus, the PSA screening method for early detection of prostate cancer is flawed by potential false positive and false negative results (sensitivity 90%; specificity 10-31%) (Thompson et al., 2004; Hessels et al., 2004; Keetch et al. 1994). False positives may lead to additional medical procedures that have potential risks, represent significant financial costs, and create anxiety for the patient and his family. Actually, only 25 to 30 percent of men who have a biopsy due to elevated PSA levels are diagnosed with prostate cancer (Keetch et al., 1994). Several modifications of the standard PSA test have been developed, and may be beneficial for select populations (Caplan and Kratz, 2002). However, uncertainty about the natural progression of prostate cancer and inherent limitations of PSA test raises serious concerns about the reliability and potential benefits of universal screening, and the recommendations of various organizations are conflictive (Caplan and Kratz, 2002).
Attempts to relate cancer-related PSA to PSA density using transrectal ultrasound or to relate PSA to velocity of change with time have been helpful but flawed (Jain et al., 2002). PSA forms complexes with various serum factors, including alpha 1-antichymotrypsin, and such complex formation is significantly higher in prostate carcinoma (PC) than in benign prostatic conditions; in general, the higher the proportion of free PSA, the lower the risk of cancer (Jain et al., 2002). Since there is a tendency to biopsy all individuals with PSA values above 3.5-4.0, using the “free” PSA to total PSA ratio could reduce negative prostate biopsies by 21-35%. Therefore, the test may be helpful in deciding whether a biopsy should be done. However, PSA cannot be used as a prognostic marker.
A variety of prognostic markers have come recently into vogue as prognostic indicators in prostate cancers. For example, DNA aneuploidy in prostate cancers correlates with a higher stage disease and shortened survival. The role of MIB-1 labeling index as a measure of proliferation, bcl-2 expression, loss of E-cadherin expression, and abnormal p53 accumulation have been proposed as prognostic indicators. Recently, additional assays have been established, based on the detection of the specific serum marker EPCA-2 (sensitivity 94%, specificity 92%) (Leman et al., 2007), and non-invasive detection methods of prostate cancer in body fluids such as urine and ejaculates based on over expression of telomerase (sensitivity 58%, specificity 100%) or the DD3 (PCA3) gene (sensitivity 67%, specificity 83%) (Hessels et al., 2004), and hyper-methylation of a four-gene cohort including glutathione S-transferase P1 (GSTP1) (theoretical sensitivity 73%, theoretical specificity 98%) (Hoque et al., 2005).
Epigenetic alterations, including hypermethylation of gene promoters, are also early events in neoplastic progression (Hanahan et al., 2000). Such alterations are believed to contribute to the neoplastic process by transcriptional silencing of tumor suppressor gene expression (Jones et al., 2002). Thus, methylated genes can serve as biomarkers for early detection of cancer (Fackler et al. 2004). In past years, several qualitative and quantitative PCR methods based on methylation of single genes (such as glutathione S-transferase P1 (GSTP1), specificity 79%; Cairns et al., 2001) or multiple-gene cohort (such as P16/ARF/MGMT/GSTP1, theoretical sensitivity 73%, theoretical specificity 98%; Hoque et al., 2005) and, recently, a multiplexed urine assay consisting of 3 methylation markers, GSTP1, RARB, and APC (sensitivity 55%, specificity 80%) has been developed (Vener et al., 2008). However, these detection methods are yet to be improved in both sensitivity and specificity, and most importantly, they are unsuitable for the detection of early stages of prostate cancer (Vener et al., 2008; Tokumaru et al., 2004).
However, the search to identify “ideal” marker(s) that would foretell disease progression and aggressiveness in newly diagnosed prostate cancers is ongoing. Cell surface proteins that modulate cell-cell and cell-extracellular matrix interactions are currently subjects of intense research in cancer biology. In particular, galectins, a family of beta-galactoside binding lectins, have been proposed to mediate diverse biological processes such as embryogenesis (Ahmed et al., 2004), inflammation (Rabinovich et al., 2002), apoptosis (Liu et al., 2000), and tumor metastasis (van den Brule et al., 2004).
Therefore, markers that would rigorously diagnose the presence of the disease in the early stages and serve as an indicator of disease progression and aggressiveness in prostate cancer have yet to be identified.